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A double-blind, randomized, controlled phase I study to assess the safety, immunogenicity, and antibody persistence of a new group A conjugate vaccine (PsA-TT) in volunteers aged 18 to 35 years was previously performed. Subjects received one dose of either the PsA-TT conjugate vaccine, meningococcal A/C polysaccharide vaccine (PsA/C), or tetanus toxoid vaccine. The conjugate vaccine was shown to be safe and immunogenic as demonstrated by a standardized group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and by a serum bactericidal antibody (SBA) assay using rabbit complement (rSBA). This report details further analysis of the sera using four additional immunologic assays to investigate the relationship between the different immunoassays. The immunoassays used were an SBA assay that used human complement (hSBA), a group A-specific IgG multiplexed bead assay, and two opsonophagocytic antibody (OPA) assays which used two different methodologies. For each vaccine group, geometric mean concentrations or geometric mean titers were determined for all assays before and 4, 24, and 48 weeks after vaccination. Pearson's correlation coefficients were used to assess the relationship between the six assays using data from all available visits. An excellent correlation was observed between the group A-specific IgG concentrations obtained by ELISA and those obtained by the multiplexed bead assay. hSBA and rSBA titers correlated moderately, although proportions of subjects with putatively protective titers and those demonstrating a > or = 4-fold rise were similar. The two OPA methods correlated weakly and achieved only a low correlation with the other immunoassays. The correlation between hSBA and group A-specific IgG was higher for the PsA-TT group than for the PsA/C group.

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Knee prosthetic designs that increase quadriceps moment arm can reduce quadriceps tension and patellofemoral compressive forces. Six knees from cadavers were tested on the Oxford knee rig, which simulates closed chain knee extension under load. Three conditions were tested sequentially for each knee: Normal, Control (implanted with the Osteonics 7000 knee design), and Scorpio (implanted with the Osteonics Scorpio design). The center of flexion-extension of the Scorpio design was 10 mm posterior to that of Control that served to lengthen the quadriceps moment arm. An electromagnetic tracking system measured dynamic knee kinematics, and a uniaxial load cell measured quadriceps tension. The Scorpio design reduced quadriceps tension when compared with the Normal or Control knee ranging from 5% to 20%. This was statistically significant at flexion angles greater than 50 degrees. In three knees, the patellar component was instrumented with a triaxial load cell that measured patellofemoral forces. Patellofemoral forces were lower with the Scorpio design compared with the Control. Increasing quadriceps lever arm reduces quadriceps forces and can facilitate activities of daily living and enhance patient rehabilitation. Reduced quadriceps forces may result in reduced patellofemoral forces that can have a beneficial effect on anterior knee pain, patellar component wear, and loosening.

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This study investigated immunological responses to Staphylococcus aureus bone infection. Because considerable immunological information is available on the mouse, a murine model of acute hematogenous osteomyelitis was established. Osteomyelitis was created in the proximal tibia of C3H/HeJ mice by a tibial epiphyseal fracture followed by intravenous bacterial inoculation with Staphylococcus aureus (strain LS-1). Swelling and warmth of the limb was found, and following limb exposure, abscess formation was evident in the proximal tibia. Histological examination revealed distortion primarily at the hypertrophic zone of the physis and polymorphonuclear leukocyte infiltration throughout the damaged area of the proximal tibia. Local infection was demonstrated at the fracture site, evidenced by the recovery of Staphylococcus aureus following microbiological analysis of tissue specimens. Polymerase chain reaction was utilized to detect 16S ribosomal prokaryotic nucleic acid to demonstrate that the diagnosis of osteomyelitis could be established in the absence of conventional microbiological techniques. The infected mice had an increase of circulating large leukocytes (granulocytes) and an elevation of total serum immunoglobulin. Flow cytometry revealed significant increases in splenic B lymphocytes and in lymph-node CD4+ T lymphocytes. These results indicate that an experimental model of acute hematogenous osteomyelitis that closely resembles the pathology of the disease in humans may be consistently induced in mice. Furthermore, marked immunological changes may be observed in response to the Staphylococcus aureus bone infection.

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The polypeptide, poly-l-tyrosine (PTYR) was incorporated into hydroxyethyl starch (HES) microspheres to modify the surface hydrophobicity in order to allow subsequent radioiodination and assessment of uptake into the intestinal mucosa following oral administration. The HES microspheres were prepared by a crosslinking polymerization process and characterized for particle size, peptide content and surface morphology. The hydrophobicity of the characterized microspheres was assessed by two techniques-water uptake (swelling) of the microspheres and contact angle measurement using the sessile drop method. Spherical microspheres containing PTYR were prepared with a greater than 80% loading efficiency in the 1-10 microns size range. The surface morphology suggested localization of the PTYR at the surface proportionate to the loading. The percent water uptake of the blank HES microspheres was 87%, whereas that of the 5, 10 and 20% PTYR/HES microspheres was 84%, 61% and 55%, respectively. HES/PTYR was polymerized as films to facilitate contact angle measurement. A monotonical increase in the contact angle was observed as the concentration of the PTYR was increased to 20%. Contact angle of pure HES (0% PTYR) films was 16 degrees and for the PTYR-containing films was 29 degrees for 5% PTYR, 39 degrees for 10% and 57 degrees for 20%. The hydrophobicity of the HES microsphere system could be increased by the incorporation of polytyrosine thereby paving the way to radioiodinate the microspheres and perform uptake studies in an animal model.

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A recently reported approach to the prediction of blood-brain drug distribution uses the general linear free energy equation to correlate equilibrium blood-brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; pi2H, solute dipolarity or polarizability; alpha2H and beta2H, the hydrogen bond acidity or basicity, and Vx, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood-brain barrier in the rat. The permeability (logPS) of the blood-brain barrier to a chemically diverse series of compounds was measured using a short duration vascular perfusion method. LogPS data were correlated with calculated solute descriptors, and octanol-water partition coefficients (logP(oct)) for comparison. It is shown that a general linear free energy equation can be constructed to predict and interpret logPS values. The utility of this model over other physicochemical descriptors for interpreting logPS and logBB values is discussed.

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It is shown that the octanol-water partition coefficient (Poct) cannot be used to predict blood brain distribution (BB) rectilinearly, but can be combined with Abraham solute descriptors to yield a predictive regression equation, eq (15), in which the solute descriptors sigma alpha H2 and sigma beta H2 are the overall summation hydrogen-bond acidity and basicity respectively. It is also demonstrated that of the various predictive models now available, that of Abraham, Chadha and Mitchell, eq (14), still yields the best results on a new test set of drug molecules; where the other solute descriptors are: R2, an excess molar refraction; pi H2, the dipolarity/polarisability; and Vx the characteristic volume of McGowan. Thus, solute dipolarity/polarizability, hydrogen-bond acidity and hydrogen-bond basicity favour blood, and solute size favours brain. logBB = +0.055 + 0.203logPoct - 0.507 sigma alpha H2 - 0.500 sigma beta H2 n = 49 rho = 0.9491 sd = 0.201 F = 136.1 (15) logBB = -0.038 + 0.198R2 - 0.607 pi H2 - 0.715 alpha H2 - 0.698 beta H2 + 0.995Vx n = 57 rho = 0.9522 sd = 0.197 F = 99.2 (14)

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The in vitro response of peripheral blood mononuclear cells (MNC) from patients with cemented total hip or knee arthroplasties, and control individuals, to polymethylmethacrylate (PMMA) was assessed by cell proliferation, cytokine production, and molecular techniques. After seven days in culture, a dose-dependent proliferative response to PMMA stimulation was observed in MNC from fifteen normal individuals. A concomitant dose-dependent production of both IL-1 beta and IL-2 in response to PMMA stimulation was detected. Reverse transcription-polymerase chain reactions (RT-PCR) indicated that both IL-1 beta and IL-2 mRNA was present after 48 hours in culture with PMMA. Cellular proliferation and cytokine production (both IL-1 beta and IL-2) in 10 patients with stable, painless, well-functioning, cemented arthroplasties was significantly lower (p < 0.025) than normal controls and patients with aseptically loosened, painful, arthroplasties. The findings suggest that patients with stable cemented total joint arthroplasties are either inherently or adaptively less responsive to PMMA at a cellular level.

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It is shown that neither the set of directly determined blood-brain concentration ratios (BB) of Young and Mitchell nor the set of indirectly obtained values of Abraham and Weathersby are suitable for the construction of a general equation for the interpretation and prediction of log BB values. However, combination of both sets leads to the general equation log BB = -0.038 + 0.198R2 - 0.687 pi H2 - 0.715 alpha H2 - 0.698 beta H2 + 0.995Vx (n = 57, rho = 0.9522, sd = 0.197, F = 99.2), where the solute descriptors are R2, an excess molar refraction; pi H2, the dipolarity/polarizability, alpha H2 and beta H2, the effective or summation hydrogen-bond acidity and basicity; and Vx, the characteristic volume of McGowan. Thus solute dipolarity/polarizability, hydrogen-bond acidity, and hydrogen-bond basicity favor blood, and solute size, as Vx, favors brain. Methods are given for the estimation of solute descriptors through fragment schemes, so that log BB values themselves may be obtained simply from knowledge of solute molecular structure.

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A general linear solvation energy equation has been used to analyze published partition coefficients in the systems water-octanol (613 solutes), water-hexadecane (370 solutes), water-alkane (200 solutes), and water-cyclohexane (170 solutes). The descriptors used in the equation are R2, an excess molar refraction; phi H2, the solute dipolarity/polarizability; sigma alpha H2 and sigma beta H2, the effective solute hydrogen-bond acidity and basicity; and Vx, the characteristic volume of McGowan. It is shown that the water-octanol partition coefficient is dominated by solute hydrogen-bond basicity, which favors water, and by solute size, which favors octanol, but solute excess molar refraction and dipolarity/polarizability are also significant. For the water-alkane partition coefficients, the same factors are at work, together with solute hydrogen-bond acidity as a major influence that favors water. An analysis of 288 delta log P values shows that solute hydrogen-bond acidity is the major factor but that solute hydrogen-bond basicity and, to a lesser extent, solute dipolarity/polarizability and size are also significant factors that influence the delta log P parameter.

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